3-(amino/dialkylamino)-3-cyano-5alpha-androstan-17beta-ols and esters, and intermediates thereto



United States Patent '3 (AMINO/DIALKYLAMINO) 3 CYANO Six-AN- Thisinvention relates to 3-aminated 17-oxygenated 3- cyanoandrostanes andprocesses for the manufacture thereof. More particularly, this inventionprovides new and useful chemical compounds of the formula wherein Rrepresents hydrogen or an alkanoyl radical and Am represents anoptionally-alkylated amino radical.

Among the alkanoyl radicals represented by R, especially lower alkanoylradicals are preferred, which is to say radicals of the formula 1 O J-lower alkyl Illustrative of the lower alkyl grouping called for aremethyl, ethyl, propyl, isopropyl, butyl, isobutyl, secbutyl, tert-butyl,pentyl, neopentyl, hexyl, isohexyl, heptyl, and like monovalent,saturated, acyclic, straightor branched-chain hydrocarbon groupings ofthe formula wherein n is a positive integer less than 8.

Am in the generic formula for compounds of this invention subsumes boththe primary amino radical, -NH and tertiary amino radicals resultingfrom the substitution of 2 alkyl radicals therein. Optimally althoughnot necessarily exclusively adapted to such substitution are alkylradicals containing fewer than 5 carbon atoms, i.e., methyl, ethyl,propyl, and the variously isomeric butyl radicals hereinabovecontemplated.

Equivalent to the foregoing basic amines for the purposes of thisinvention are corresponding acid addition salts of the formula useful byreason of their valuable pharmacological properties. Thus, for example,they are anabolic and androgenic agents. It follows that theintermediates, whence these compounds derive are likewise valuable.

Manufacture of the primary amines hereof proceeds by contacting anappropriate androstanone (R being defined as before) with potassiumcyanide and ammonium chloride in cold aqueous ethanol. The amine soproduced is admixed with the corresponding cyanohydrin, from which it isseparated by dissolution in propanolic hydrogen chloride. Additionalamine is obtained by saturating a cold methanol solution of thecyanohydrin with ammonia.

The tertiary amines hereof are obtained by melting an appropriateandrostanone It H3O 0-O-lower alkyl and contacting the melt duringseveral hours with an appropriate alkylamine, dissolving the resultant3-alkylimin'o derivative in dichloromethane and adding a correspondingalkyl iodide to quaternize the nitrogen, dissolving the quaternary iminein acetonitrile and mixing the solution with aqueous potassium cyanideto give the tertiary amino 17-ester, and hydrolyzing the ester groupingwith aqueous methanolic hydrogen chloride.

Conversion of the amine bases hereof to acid addition salts isaccomplished by simple mixing of a base with 1 equivalent of any ofvarious inorganic and strong organic acids, the anionic portion of whichconforms to X as hereinabove defined.

The following examples describe in detail compounds illustrative of thepresent invention and methods which have been devised for theirmanufacture. However, the invention is not to be construed as limitedthereby, either in spirit or in scope, since it will be apparent tothose skilled in the art of organic synthesis that many modifications,both of materials and of methods, may be practiced without departingfrom the purpose and intent of this disclosure. Throughout the exampleshereinafter set forth, temperatures are given in degrees centigrade andrelative amounts of materials in parts by weight, except as otherwisenoted.

Example 1 A. 3-cyan0-5a-andr0stane-3,17fi-di0l.-TO a solution of partsof 17B-hydroxy-5a-androstan-3-one in 1200 parts of anhydrous alcohol at0-5 is added, With agitation, a solution of 22 parts of potassiumcyanide and approximately 18 parts of ammonium chloride in 200 parts ofwater. The resultant mixture is allowed to warm to room temperatureduring agitation for 3 hours, whereupon it is chilled to 05 and dilutedwith 3 volumes of cold water. The insoluble solids thrown down arefiltered off, washed with water, and suspended in 400 parts of2-propan0l. Approximately 80 parts of a 40% solution of hydrogenchloride in 2-propanol is introduced. The resultant mixture ismaintained with agitation for 5 minutes, then diluted with 3 volumes ofwater. The insoluble solids are 3-cyano-5a-androstane-3,l7fl-diol which,filtered off and dried in air, melts at 210-213.

B. 3-amin0-3-cyano-5a-androstan-I7/3-0l.The filtrate deriving fromisolation of 3-cyano-5a-androstane-3,17,8- diol in the foregoing Part Aof this example is neutralized with sodium hydroxide. The insolublesolids thrown down, filtered off and successively recrystallized frommethanol and acetone, afford 3-amino-3-cyano-5aandrostan-UB-ol, meltingat ISO-164 and further characterized by a specific rotation, referred tothe D line of sodium and at 26 in methanol solution, of t-19. Theproduct has the formula H O H N l 1 Example 23-amin0-3-cyan0-5a-androstan-17/3-0l.A solution of 10 parts of3-cyano-5u-androstane-3,l7fi-diol in 80 parts of methanol at -5" issaturated with ammonia gas. The product thrown down is3-amino-3-cyano-5a-androstan- 17 8-01, which is filtered off andrecrystallized as described in Example 1B.

Example 3 H30 moon W Example 4 A. 176 acetoxy 3 methylimino 5aandr0stane.- Methylamine is passed into (molten)17fi-acetoxy-5aandrostan-3-one at approximately 150 during vigorousagitation over a period of 5 hours. The resultant mixture is cooled toroom temperature and thereupon taken up in dichloromethane. Thedichloromethane solution, washed with water, dried over anhydrous sodiumsulfate, and stripped of solvent, affordsl7B-acetoxy-3-rnethylimino-5a-androstan as a viscous oil.

B. 17;? acetoxy 3 methylimz'no 5a androstane methi0dide.To a solution of19 parts of l7/3-acetoxy-3- methylimino-Sa-andrOstane in approximately120 parts of dichloromethane is added 140 parts of methyl iodide. Theresultant mixture is allowed to stand at room temperatures for 3 /2hours, then poured into approximately 500 parts of ether. Insolublesolids are 17fl-acetoxy-3- methylimino-Sa-andmstane methiodide, which ispromptly isolated by filtration.

C. 175 acetoxy-3-cyano-3-dimethylamin0 5a androstane.A solution ofapproximately 20 parts of 17/3- acetoxy-3-methylimino-5a-androstanemethiodide in approximately 360 parts of acetonitrile is poured into asolution of 1 1 parts of potassium cyanide in 200 parts of water. Theresultant mixture is maintained with agitation at room temperatures for40 minutes, then poured into 3000 parts of ice water. The mixture thusobtained is maintained with agitation for 15 minutes, then filtered. Thelight tan powder thus isolated, recrystallized from a mixture of dioxaneand water, affords 17/3-acetoxy-3-cyano- 3-dimethylamino-5a-androstanemelting in the range 152- The product has the formula H3O OCOCH;

Example 5 EEC OH 3) 2 J C N 5 What is claimed is: 1. A compound of theformula C 0 it wherein R represents a member of the group consisting ofhydrogen and a radical of the formula O lower alkyl and Am represents amember of the group consisting of radicals of the formulas in which nrepresents a positive integer less than 5.

UNITED STATES PATENTS 7/ 6 1 Ercoli 260--397.4 3/62 Gianigiacomo260397.4

LEWIS GOTTS, Primary Examiner.

1. A COMPOUND OF THE FORMULA